Atena Zahedi, PhD | Stem Cell Research Center
Competition Sponsor: US National Academy of Medicine
Award year: 2021
Transplantation of human neural stem cells (hNSC) to repair damaged tissues in traumatic injuries has shown promise in pre-clinical studies and early clinical trials. Spinal cord injury (SCI) is marked by a secondary injury phase characterized by an ischemic oxidative microenvironment, secreted pro-inflammatory factors, and mitochondria dysfunction in the surviving damaged cells/tissues. We hypothesize that survival and engraftment of transplanted hNSCs is hindered in a manner reliant on their intrinsic mitochondrial properties. Mitochondria are vital for the bioenergetics of cells during times of high demand such as proliferation, stem cell differentiation, and migration. To test this hypothesis, we utilize tissue-derived hNSC lines derived in our lab, previously tested for their repair potential (efficacy) in restoring functional recovery after SCI. Transcriptomic analysis comparing an efficacious line (UCI161) versus a non-efficacious line (UCI152) revealed differences in “mitochondria fitness traits” (MFTs): mitochondrial bioenergetics, mitochondrial biogenesis, permeability transition and redox potential, and autophagy and mitophagy. We identified drug candidates to target mitochondrial function by screening FDA-approved mitochondrial drugs. Treatment of hNSC with a bioenergetics-enhancing drug led to increased mitochondrial hyperfusion and tunneling nanotube (TNT) formation, whereas treatment of hNSC with a biogenesis drug led to enhanced mitochondria mass and proliferation in UCI161. MTT, autophagy analysis, mitochondria membrane potential (MMP) and ATP analysis revealed UCI161 were better responders to bioenergetic drugs, where UCI152 responded optimally to biogenesis enhancement. hNSC with improved mitochondrial response capabilities show promise for translation to neuro-transplantation in chronic traumatic injuries and neurodegenerative diseases characterized by mitochondria dysfunction and loss of bioenergetics.